Observation of secondary nucleation in drowning-out crystallization using FBRM

Keigo Hanaki, Izumi Hirasawa

    Research output: Contribution to journalArticle

    2 Citations (Scopus)

    Abstract

    The nucleation behavior of an active pharmaceutical ingredient (API) is investigated in semi-batch drowning-out crystallization. A methanol solution of the API was fed in a short period into a well-mixed anti-solvent at low temperature. The effect on nucleation behavior of the amount of seed crystals and concentration of API methanol solution to be fed was investigated using in-line particle monitoring technique (FBRM). Despite the presence of seed crystals in anti-solvent into which the API solution was fed, nucleation took place after an induction period from feeding in some experiments, and it was found that the addition of seed crystals is effective to control the induction period and to enhance nucleation after the induction period. As for feed concentration, at high feed concentration, generation of nuclei during feeding was observed and then a supersaturated slurry of fine particles was obtained; however, at low feed concentration, anti-solvent became clouded locally during feeding and then clear supersaturated solution was obtained. At high feed concentration, it was also observed from time courses of FBRM chord count for several size classes that fine particles generated during feeding grew very slowly during the induction period, and rapid nucleation took place accompanied with agglomeration of fine particles and subsequent dispersion with generating nuclei.

    Original languageEnglish
    Pages (from-to)386-392
    Number of pages7
    JournalJournal of Chemical Engineering of Japan
    Volume42
    Issue number6
    DOIs
    Publication statusPublished - 2009 Jun 20

    Fingerprint

    Crystallization
    Nucleation
    Drug products
    Pharmaceutical Preparations
    Crystals
    Methanol
    Agglomeration
    Monitoring
    Experiments
    Temperature

    Keywords

    • Crystallization
    • Induction period
    • Secondary nucleation

    ASJC Scopus subject areas

    • Chemical Engineering(all)
    • Chemistry(all)

    Cite this

    Observation of secondary nucleation in drowning-out crystallization using FBRM. / Hanaki, Keigo; Hirasawa, Izumi.

    In: Journal of Chemical Engineering of Japan, Vol. 42, No. 6, 20.06.2009, p. 386-392.

    Research output: Contribution to journalArticle

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